warfarin

Absorption: Well absorbed from the GI tract after oral administration.

Distribution: Minimally distributed to tissues.

Protein Binding: 99%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP2C9 isoenzyme, with some metabolism via the CYP3A4 isoenzyme; the CYP2C9 isoenzyme exhibits genetic polymorphism (intermediate or poor metabolizers may have significantly ↑ (S)-warfarin concentrations and an ↑ risk of adverse reactions).

Half-Life: 42 hr.

Time/Action Profile ⬆ ⬇

(effects on coagulation tests)

ROUTE	ONSET	PEAK	DURATION
PO	36–72 hr	5–7 days‡	2–5 days‡

‡At a constant dose

‡After discontinuation

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Uncontrolled bleeding;
Open wounds;
Active ulcer disease;
Recent brain, eye, or spinal cord injury or surgery;
Severe hepatic impairment;
Uncontrolled hypertension;
OB: Pregnancy.

Use Cautiously in:

Malignancy;
History of ulcer, liver disease, or acute kidney injury;
History of poor compliance;
Asian patients or those who carry the CYP2C9*2 allele and/or the CYP2C9*3 allele, or with the VKORC1 AA genotype (↑ risk of bleeding with standard dosing; lower initial doses should be considered);
Rep: Women of reproductive potential;
Pedi: Has been used safely in children, but may require more frequent INR assessments;
Geri: Appears on Beers list. ↑ risk of major bleeding when compared to direct acting oral anticoagulants (DOACs) in older adults. Avoid starting as initial therapy for treatment of nonvalvular atrial fibrillation or venous thromboembolism unless alternative options (DOACs) are contraindicated or there are significant barriers to their use. If already using warfarin, it may be reasonable to continue treatment, especially if INR is well controlled (i.e., >70% time in therapeutic range) and no adverse effects.

Adv. Reactions/Side Effects ⬆ ⬇

Derm: dermal necrosis

GI: cramps, nausea

GU: CALCIPHYLAXIS

Hemat: BLEEDING

Misc: fever

Interactions ⬆ ⬇

Drug-drug:

Androgens, capecitabine, cefotetan, chloramphenicol, clopidogrel, disulfiram, fluconazole, fluoroquinolones, itraconazole, metronidazole (including vaginal use), thrombolytics, eptifibatide, tirofiban, sulfonamides, quinidine, quinine, NSAIDs, valproates, and aspirin may ↑ risk of bleeding.
Chronic use of acetaminophen may ↑ risk of bleeding.
Chronic alcohol ingestion may ↓ effectiveness; if chronic alcohol abuse results in significant liver damage, may ↑ risk of bleeding due to ↓ production of clotting factors.
Acute alcohol ingestion may ↑ risk of bleeding.
Barbiturates, carbamazepine, rifampin, and hormonal contraceptives containing estrogen may ↓ levels and effectiveness.

Drug-Natural Products:

St. John’s wort may ↓ levels and effectiveness.
↑bleeding risk with anise, arnica, chamomile, clove, dong quai, fenugreek, feverfew, garlic, ginger, ginkgo, Panax ginseng, and licorice.

Drug-Food:

Ingestion of large quantities of foods high in vitamin K content (see list in Food Sources for Specific Nutrients) may antagonize the anticoagulant effect of warfarin.

Route/Dosage ⬆ ⬇

PO (Adults ): 2–5 mg/day for 2–4 days; then adjust daily dose by results of INR. Initiate therapy with lower doses in older adults or in Asian patients or those with CYP2C9*2 and/or CYP2C9*3 alleles or VKORC1 AA genotype.
PO (Children >1 mo): Initial loading dose: 0.2 mg/kg (maximum dose: 10 mg) for 2–4 days; then adjust daily dose by results of INR. Use 0.1 mg/kg if hepatic impairment is present. Maintenance dose range: 0.05–0.34 mg/kg/day.

Availability ⬆ ⬇

(Generic available)

Tablets: 1 mg; 2 mg; 2.5 mg; 3 mg; 4 mg; 5 mg; 6 mg; 7.5 mg; 10 mg

Assessment ⬆ ⬇

Assess for signs of bleeding and hemorrhage (bleeding gums; nosebleed; unusual bruising; tarry, black stools; hematuria; fall in hematocrit or BP; guaiac-positive stools, urine, or nasogastric aspirate).
Assess for additional or ↑ thrombosis.

Lab Test Considerations:

Monitor PT, INR, and other clotting factors frequently during therapy and more frequently in patients with renal impairment. In general, an INR of 2–3 is recommended for most patients receiving warfarin.
Asian patients and those who carry the CYP2C9*2 allele and/or the CYP2C9*3 allele, or those with VKORC1 AA genotype may require more frequent monitoring and lower doses.
- Patients >60 yr exhibit greater than expected PT/INR response. Monitor for side effects at lower therapeutic ranges.
- May be more difficult to achieve and maintain therapeutic PT/INR ranges in children. Assess PT/INR levels more frequently.
- Monitor hepatic function and CBC before starting and periodically throughout therapy.
- Monitor stool and urine for occult blood before and periodically during therapy.

Toxicity and Overdose:

Withholding one or more doses of warfarin is usually sufficient if INR is excessively elevated or if minor bleeding occurs. If overdose occurs or anticoagulation needs to be immediately reversed, the antidote is vitamin K (phytonadione). Administration of whole blood or plasma also may be required in severe bleeding because of the delayed onset of vitamin K.

Implementation ⬆ ⬇

Do not confuse Jantoven with Janumet or Januvia.
Because of the large number of medications capable of significantly altering warfarin’s effects, careful monitoring is recommended when new agents are started or other agents are discontinued. Interactive potential should be evaluated for all new medications (Rx, OTC, herbal).
PO: Administer medication at same time each day; requires 3–5 days to reach effective levels; usually begun while patient is still on heparin.
- Do not interchange brands; potencies may not be equivalent.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy.
Instruct patient to take missed doses as soon as remembered that day; do not double doses. Inform health care provider of missed doses at time of checkup or lab tests. Inform patients that anticoagulant effect may persist for 2–5 days following discontinuation.
Instruct patient to carry identification describing medication regimen at all times and to inform all health care personnel caring for patient on anticoagulant therapy before lab tests, treatment, or surgery.
Emphasize the importance of frequent lab tests to monitor coagulation factors.
Review foods high in vitamin K (see Food Sources for Specific Nutrients). Patient should have consistent limited intake of these foods, as vitamin K is the antidote for warfarin, and alternating intake of these foods will cause coagulation to fluctuate. Advise patient to avoid cranberry juice or products during therapy.
Caution patient to avoid IM injections and activities leading to injury. Instruct patient to use a soft toothbrush, not to floss, and to shave with an electric razor during warfarin therapy. Advise patient that venipunctures and injection sites require application of pressure to prevent bleeding or hematoma formation.
Advise patient to notify health care provider of unusual bleeding or bruising (bleeding gums; nosebleed; black, tarry stools; hematuria; excessive menstrual flow) and pain, color, or temperature change to any area of the body.
Notify patient with deficiency in protein C and/or S mediated anticoagulant response that they may be at ↑ risk for tissue necrosis.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications, especially alcohol, aspirin or other NSAIDs.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective contraception during and for 1 mo after last dose. Advise patient to notify health care provider if pregnancy is planned or suspected or if breastfeeding.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇